Acute liver failure (ALF) is a fatal clinical syndrome characterized by an abrupt loss of hepatocellular function, which causes coagulopathy, jaundice and encephalopathy. In our country, acute liver failure with a histological appearance of hepatitis is classified as fulminant hepatitis (FH) or late-onset hepatic failure (LOHF). Fulminant hepatitis is a disease with extremely poor prognosis, for which liver transplantation has solely been established as a treatment method that improves the lifesaving rate thereof. Due to the donor shortage and the like, however, the executing rate thereof is only just over 20%, and the lifesaving rate by a medical treatment is as low as 20-50%. Therefore, it is an urgent task to develop a new treatment method with verified effectiveness.
Hepatocyte growth factor (HGF) is a growth factor having a potent promoting effect on liver regeneration, which is isolated from the plasma of patients with fulminant hepatitis (e.g., see patent document 1). Since HGF has been found to have, in addition to a hepatocyte proliferative or regenerative action (e.g., see non-patent documents 1 and 2), a wide variety of physiological activities such as a hepatocyte-protective action (e.g., see non-patent documents 3-5) by anti-apoptosis, an anti-fibrotic action and the like, a treatment of hepatic failure by HGF is expected. Although the effectiveness has been confirmed in vitro and in animal models, the efficacy, safety and the like of HGF in the human body are still unclear. Particularly, the lifesaving effect in acute liver failure with extremely poor prognosis such as fulminant hepatitis and late onset hepatic failure, and whether HGF administration is effective for the prevention of acute liver failure associated with encephalopathy without coma from becoming fulminant cannot be predicted at all. In addition, a possibility of HGF administration causing side effects such as decreased blood pressures, renal toxicity and the like was suggested in preclinical safety tests. However, an administration protocol that avoids those side effects in clinical situations has not been established.
Moreover, a technique and an index for monitoring the efficacy of HGF, i.e., liver regeneration promoting action and anti-apoptotic action, in the human body have not been developed heretofore. In the animal experiment level, the liver regeneration promoting action of the recombinant human HGF has been appreciated in view of the increased liver weight and increased serum albumin value thereby (non-patent document 6). However, the evaluation based on an increase in the liver weight (liver volume) cannot provide a real-time evaluation of liver regeneration induction, since the time necessary for increasing the weight (volume) after the induction of liver regeneration is long. Moreover, the serum albumin value reflects improved liver synthesizability as the result of liver regeneration, and is not suitable as an index for liver regeneration per se.
α-Fetoprotein (AFP) is a glycoprotein with a molecular weight of 67 kDa, which is found in the human fetal serum, and is practically used as a serum immunological diagnosis marker for hepatocellular carcinoma. In animal disease models, AFP is expressed in immature hepatocytes such as liver progenitor cell, hepatoblast and the like, and clinically, it has been reported that the serum AFP value reflects liver regeneration and mildly increases in fulminant hepatitis and chronic hepatitis (non-patent document 7).
On the other hand, soluble Fas is a Fas present on a cell surface, which is cleaved and released into the blood, and binds to Fas ligand to antagonize the binding of Fas and Fas ligand on the cell surface, thus suppressing apoptosis.
In fulminant hepatitis, the blood HGF value important for the prediction of prognosis remarkably increases. However, since a correlation is not found between blood HGF value, and serum AFP value and soluble Fas value, there was no prediction on the utilizability of AFP and soluble Fas as an index (efficacy biomarker) for the treatment effect of exogenous HGF administration.